Exploiting Protein Corona around Gold Nanoparticles Conjugated to p53 Activating Peptides To Increase the Level of Stable p53 Proteins in Cells.
Kian Ping ChanSheng-Hao ChaoJames Chen Yong KahPublished in: Bioconjugate chemistry (2019)
Therapeutic peptides suffer from major drawbacks such as peptide degradation in vivo due to proteolysis. Gold nanoparticles (AuNPs) are an effective carrier for therapeutic peptides that improve their stability in vivo, while also enabling nonspecific adsorption of complementary proteins to enhance their effectiveness. Using p53 peptide as a model known to disrupt the intracellular MDM2-p53 protein-protein interaction which tags the endogenous p53 proteins for degradation, we conjugated p53 peptides to AuNPs (AuNP-p53) and examined the functionality of AuNP-p53 to release the endogenous p53 proteins from being tagged for degradation, thereby increasing the level of stable p53 proteins in acute myeloid leukemia 2 (AML2) cells. We found that AuNPs did not just protect conjugated p53 peptides from trypsin degradation, but also helped to recruit 56.5% and 26.4% of total MDM2 and p53 proteins in the cells to form a protein corona around AuNP-p53. The proximity of MDM2/p53 complexes and p53 peptide on the surface of AuNP-p53 facilitated the action of p53 peptides to cause a sustained elevation of the p53 level in AML2 cells up to 6 h, which was not possible with free p53 peptide alone at the same concentration. Even a 20-fold higher concentration of free p53 peptide caused only a short-lived elevated p53 level of 1 h. The outcome of this study highlights the utility of combining conjugated ligands and complementary protein adsorption on nanoparticles to improve the biological functionality of the therapeutic ligands.
Keyphrases
- induced apoptosis
- protein protein
- gold nanoparticles
- cell cycle arrest
- amino acid
- photodynamic therapy
- small molecule
- randomized controlled trial
- signaling pathway
- systematic review
- acute myeloid leukemia
- endoplasmic reticulum stress
- cell death
- binding protein
- cell proliferation
- allogeneic hematopoietic stem cell transplantation
- acute lymphoblastic leukemia
- reactive oxygen species
- reduced graphene oxide